title: Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release.
abstract: The complement system is a potent component of the innate immune response, promoting inflammation and orchestrating defense against pathogens. However, dysregulation of complement is critical to several autoimmune and inflammatory syndromes. Elevated expression of the proinflammatory cytokine IL-1β is often linked to such diseases. In this study, we reveal the mechanistic link between complement and IL-1β secretion using murine dendritic cells. IL-1β secretion occurs following intracellular caspase-1 activation by inflammasomes. We show that complement elicits secretion of both IL-1β and IL-18 in vitro and in vivo via the NLRP3 inflammasome. This effect depends on the inflammasome components NLRP3 and ASC, as well as caspase-1 activity. Interestingly, sublethal complement membrane attack complex formation, but not the anaphylatoxins C3a and C5a, activated the NLRP3 inflammasome in vivo. These findings provide insight into the molecular processes underlying complement-mediated inflammation and highlight the possibility of targeting IL-1β to control complement-induced disease and pathological inflammation.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Federica
authors.initials: F
authors.lastname: Laudisi
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.forename: Maximilien
authors.initials: M
authors.lastname: Evrard
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Barbara
authors.initials: B
authors.lastname: Mandriani
authors.forename: Matheswaran
authors.initials: M
authors.lastname: Kandasamy
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Baalasubramanian
authors.initials: B
authors.lastname: Sivasankar
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mortellaro
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics; D003165:Complement System Proteins / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D003183:Complement C6; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D003165:Complement System Proteins; D020170:Caspase 1